Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of ...artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.
Abstract
Introduction
histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant ...(SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile.
Methods
The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of < 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion.
Results
As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively.
Conclusion
Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021.
Support (if any):
Abstract
Introduction
A retrospective analysis was conducted to characterize diagnostic sleep testing during the 12 months before diagnosis of idiopathic hypersomnia (IH), a hypersomnolence disorder ...with no approved treatments.
Methods
IBM® MarketScan® claims data were analyzed (1/1/14–9/30/19) to identify adults with newly diagnosed IH, defined as ≥2 claims with an IH diagnosis code ≥1 day and ≤180 days apart, and without an IH diagnosis ≤12 months before cohort entry. Demographics, diagnosing physician specialty, and diagnostic sleep disorder testing (identified via claims with procedure codes for multiple sleep latency test/maintenance of wakefulness test MSLT/MWT, home sleep test, and polysomnography) were summarized. Analyses were performed on patients with IH diagnosis codes recorded in any position on the claims (“overall IH”) and in the primary position (“primary IH”) to understand the effects of applying a more specific definition of IH.
Results
Of 32,948,986 eligible people, 4,980 (0.015%) newly diagnosed IH patients were identified. Mean age was 43 years and 67% were female; those with primary IH (n=2,205; 44% of overall IH) were younger (mean age, 39 years) and more likely to be female (73%). Long sleep time was documented for 69% of the overall IH group and 67% of the primary IH group. The top 3 diagnosing physicians’ specialties were similar for overall IH/primary IH: pulmonology (23%/26%), neurology (14%/16%), and internal medicine (11%/10%). Few patients (9% overall IH; 7% with primary IH) were diagnosed in family practice. Any sleep testing was performed in 44% of overall IH and 53% of primary IH patients. Polysomnography and MSLT/MWT, the most frequently used sleep tests, were less common in overall IH (39% and 22%) than in primary IH (48% and 32%).
Conclusion
IH patients were typically diagnosed by specialists, outside of general medical practice. The most common diagnosing physicians were pulmonologists and neurologists for both the overall and primary IH groups. Objective sleep testing was more frequently documented in diagnosis of primary IH but utilization was low regardless of the definition of IH diagnosis. Further research is needed to investigate the utilization of sleep testing by clinicians for diagnosing IH.
Support (if any)
Jazz Pharmaceuticals
Abstract
Introduction
Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder with no approved treatment, characterized by excessive daytime sleepiness, prolonged sleep time, and sleep ...inertia. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses severity of IH symptoms, including symptoms related to night/inertia (component I) and day/performance (component II). Individual IHSS items measure symptom frequency, intensity, and consequences using 3- or 4-point Likert scales, yielding a total score (range, 0–50), comprising component I (range, 0–16) and component II (range, 0–34). Higher scores indicate worse symptoms. In a recent clinical trial of the efficacy and safety of lower-sodium oxybate (LXB; Xywav™) for the treatment of IH, the IHSS was a key efficacy measure.
Methods
Eligible participants 18–75 years of age with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The IHSS was completed at baseline, during OLTTOP (weeks 1, 4, and 8), and at the end of OLTTOP, SDP, and DBRWP. Change in IHSS total score from SDP to DBRWP was a key secondary endpoint.
Results
The efficacy population included 115 participants (mean±SD age, 41±14 years; 71% female). At baseline and the end of SDP, respectively, mean±SD IHSS scores were 31.6±8.3 and 15.3±8.5 for total score, 10.3±3.6 and 5.4±2.8 for component I (night/inertia), and 21.2±5.8 and 9.9±6.5 for component II (day/performance). Worsening from SDP to DBRWP was observed in patients randomized to placebo compared with LXB in IHSS total scores (estimated median difference 95% CI, −12.0 −15.0, −8.0; significant P<0.0001), component I scores (LS mean difference 95% CI, −3.9 −4.9, −2.9; nominal P<0.0001), and component II scores (LS mean difference 95% CI, −7.8 −9.6, −5.9; nominal P<0.0001). Results on all individual IHSS items reflected an improvement with LXB treatment over time during OLTTOP, which remained consistent during SDP.
Conclusion
These results support the efficacy of LXB for the treatment of IH symptoms, as assessed with the IHSS.
Support (if any)
Jazz Pharmaceuticals
Abstract
Introduction
Pitolisant was initially approved by the FDA in 2019 for the treatment of excessive daytime sleepiness in adult patients with narcolepsy; in 2020, the indication was expanded to ...include the treatment of cataplexy.
Methods
Cataplexy data from 7- or 8-week, randomized, placebo-controlled studies (HARMONY-CTP, HARMONY-1) are reviewed and summarized. In HARMONY-CTP, all patients were required to have ≥3 cataplexy attacks per week at baseline; HARMONY-1 enrolled patients with narcolepsy with or without cataplexy. Pitolisant was individually titrated to a maximum potential dose of 35.6 mg/day. The weekly (WRC) or daily (DRC) rate of cataplexy attacks was calculated from patient diaries.
Results
In HARMONY-CTP (pitolisant, n=54; placebo, n=51), mean baseline WRC was 11.7 in the pitolisant group and 9.6 in the placebo group. In the subset of HARMONY-1 patients with cataplexy (pitolisant, n=17; placebo, n=11), mean baseline DRC was 1.5 and 1.2, respectively. In HARMONY-CTP, least-squares (LS) mean change in WRC was significantly greater for pitolisant versus placebo at Week 2 (-4.1 vs 1.2; P=0.004) and continued through end of treatment (Week 7; -6.5 vs -0.1; P<0.001). In HARMONY-CTP, treatment response was observed in 66.7% of pitolisant-treated versus 25.5% of placebo-treated patients (P<0.001) for WRC reduction ≥50%, and 77.8% versus 33.3% of patients (P<0.001) for WRC reduction ≥25%. In HARMONY-1, LS mean change in DRC was significantly greater for pitolisant versus placebo at Week 5 (-1.04 vs 0.17; P=0.047) and continued through end of treatment (Week 8; -0.96 vs 0.35; P=0.035). In a pooled analysis of patients with high burden of cataplexy (≥15 attacks/week) at baseline (pitolisant, n=20; placebo, n=11), LS mean change in WRC at end-of-treatment assessment was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) versus placebo (-0.1; baseline, 23.1; final, 23.0; P=0.004). There was no evidence of rebound cataplexy after a 1-week placebo washout period.
Conclusion
Pitolisant, at once-daily doses of up to 35.6 mg, demonstrated a statistically significant and clinically meaningful reduction in the frequency of cataplexy attacks in adults with narcolepsy, including patients with a high symptom burden. Onset of response was observed within the first few weeks of pitolisant treatment.
Support (if any)
Bioprojet Pharma and Harmony Biosciences, LLC.
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